Caris Life Sciences, a leading biosciences company focused on fulfilling the promise of precision medicine, announced the presentation of data from multiple studies in which Caris Molecular Intelligence, Caris’ comprehensive tumour profiling service, was used to identify biomarkers of response to novel classes of immunotherapeutic agents. The data, presented last week at the 50th annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Illinois, shed light on potential immunotherapeutic targets in a broad range of malignancies, including colorectal cancer, triple negative breast cancer (TNBC), and metaplastic breast cancer.
“As the field of immunotherapy continues to evolve, Caris understands the importance of identifying patients who are likely to respond to the newer classes of immunotherapeutic agents that are being investigated and developed, as evidenced by our integration of routine PD-1 and PD-L1 testing in Caris Molecular Intelligence,” commented Sandeep K. Reddy, M.D., Chief Medical Officer at Caris Life Sciences. “Because PD-1 and PD-L1 cannot be found through DNA analysis alone, identification and characterization of novel, actionable targets through use of multi-technology molecular profiling is critical to enhancing our understanding of these markers of response to immunotherapy. For treating physicians, this comprehensive analysis potentially expands treatment options for a wide range and larger number of patients with various types of cancer.”
In a poster presentation last week, a team led by Zoran Gatalica, M.D., DSc, Executive Medical Director at Caris Life Sciences, presented data demonstrating the value of Caris Molecular Intelligence as a means to completely characterize colorectal tumours. In particular, the data highlight the importance of the programmed cell death protein 1 (PD-1) and its ligand, PD-L1, as markers of potential response to novel immune checkpoint inhibitors in patients with colorectal cancer (CRC) with microsatellite instability (MSI). Microsatellites are short repetitive sequences of DNA; MSI, which is detected by polymerase chain reaction (PCR)-based assays that reveal the mutated microsatellites, results from impaired DNA mismatch repair (MMR) mechanisms(i.e., when DNA errors that spontaneously occur during DNA replication are not corrected).
Dr. Gatalica and colleagues profiled 87 CRC cases for the presence of PD-1- and PD-L1-expressing cells, MMR proteins, DNA-MSI, and select cancer gene sequences (detected via next-generation sequencing [NGS]). They detected PD-1-positive intraepithelial lymphocytes (PD-1+ IEL) in 77% of MSI-H CRCs and in 38% of microsatellite-stable (MSS) CRCs. Similarly, the proportion of PD-L1+ CRCs was significantly higher in MSI-H than in MSS CRC groups, (38% vs. 13%; p=0.02); though the expression of PD-L1 in cancer cells was described as “patchy” in most cases. Expression of both PD-1+ IEL and PD-L1 cancer cells were seen in 30% of MSI-H CRCs and in 5% of MSS cancers (p=0.008).
“Immune checkpoint-inhibiting drugs interrupt interactions between immune-modulating PD-1-positive lymphocytes and the cancer-expressing ligand PD-L1, leading to tumour reduction and disease control,” noted Dr. Gatalica. “Clinicians considering initiation of immune checkpoint therapy should therefore check for the presence of PD-1 lymphocytes and cancer cell-specific PD-L1 expression, as a guide to administering these agents to appropriate patients.”
Dr. Gatalica noted that his findings are similar to those from a Phase 2 study of PD-1 antibody in patients with MSI tumours, conducted at Johns Hopkins University School of Medicine, and that more than five PD-1/PD-L1 trials are ongoing, although the data thus far are exploratory and early. “PD-1 and PD-L1 markers are not elevated at the same levels across all cancer types, meaning that the effectiveness of the anti-PD-1 immunomodulatory agents may depend on specific elevation levels,” he cautioned. “Moreover, immunotherapies are not appropriate for every solid tumour; some tumours are not associated with these specific immune responses. PD-1/PD-L1 status, however, should be evaluated before embarking upon clinical trial enrollment, as this analysis can significantly inform the patient recruitment process, and can be done easily and inexpensively via gold-standard immunohistochemistry testing.”
A separate oral presentation focused on expression of PD-L1 and other immunotherapeutic biomarkers in TNBC, an aggressive form of breast cancer in which the cancer cells lack estrogen receptors (ER), progesterone receptors (PR), and large amounts of the HER2/neu protein. This research revealed how expression of immune regulatory targets in the TNBC population suggests that immune-targeted therapies may be effective in certain patients. These findings are considered especially timely, given the growing interest in immunotherapy as a potential treatment option in TNBC and other tumor types. In the study, 511 TNBC samples underwent multiplatform molecular profiling by Caris Molecular Intelligence, which included whole genome messenger RNA (mRNA) expression, protein expression via immunohistochemistry (IHC), gene copy number changes via in situ hybridization (ISH), and gene sequencing. The researchers, led by Barbara Pockaj, M.D., of the Mayo Clinic in Phoenix, Ariz., reported an inverse correlation between PD-L1 and BRCA1, suggesting that certain TNBC patients may benefit from a combination of immunotherapy and platinum agents or PARP inhibitors. Additionally, patients with quadruple-negative breast cancer (i.e., lacking the AR protein as well as ER, PR and HER-2) were identified as another population that may benefit from immunotherapeutic agents. In particular, patients with androgen receptor (AR)-negative TNBC may benefit from therapies designed to inhibit the activity of molecules such as PD-L1, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and indoleamine 2,3-dioxygenase 1 (IDO-1).
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